Inhalant is a dosage form used for the oral or nasal inhalation of a drug formulation for administering a pharmaceutically active ingredient mainly to the lower respiratory tracts such as the trachea, bronchi, bronchiole, pulmonary alveoli, and the like.
Inhalant has been used as a topically administered formulation for thoracic diseases such as asthma, bronchitis, emphysema, and the like, and further it is recently attracting attention as means to deliver a physiologically active peptide, protein, and the like through the pulmonary alveoli to the systemic bloodstream. In general, inhalants directly deliver the active ingredient to the lungs, are therefore instantaneously effective, and require only a smaller dose of an active ingredient than an oral dosage form. As a result, this provides considerable advantage such as a reduced side effect.
Inhalants may be classified into liquid inhalants for inhaling a liquid, aerosol using a spray aerosol generator, and powder inhalants for inhaling a powdery drug. However, because of the environmental problems associated with CFC propellants, recent trends have led to powder inhalants being preferentially developed.
The most preferred form for the powder preparation used in powder inhalants (hereafter, dry powder inhalation) is a dosage form in which a micronized active ingredient is adhered to the surface of carrier particles.
It is important for a dry powder inhalation to be inhalable, in particular, it is required that the carrier and drug particles must separate well, that the micronized particles do not remain adhered to the powder dispersion device used during inhalation, and that the drug particles be uniformly dispersed in the gas phase.
Processes are presently known for the pulverization of active ingredients, such as a freeze dry method (Japanese Patent Application Laid-Open No. H06-100464), a solvent process using a spray dry method (Japanese Patent Application Laid-Open No. H11-79985), and a crystallization method (Japanese Patent Laid-Open No. H8-291073), but the use of solvent creates environmental problems and the use of solvent is not possible if the active ingredient is unstable in the solvent, prompting the need for a solvent-free preparation method.
When a dry powder inhalation is administered from a suitable inhaler device into the respiratory tract, the carrier particles would deposit in the oral cavity, throat, or larynx, but the active ingredient particulates alone would reach, and deposit on, the lower respiratiory tracts such as the trachea, bronchi, and the like. However, if a bitter tasting active ingredient is used, the bitterness felt in the oral cavity or in the throat will create much discomfort. In particular, since many pediatric and elderly patients use the device, the dry powder inhalation would not necessarily be a liked dosage form, which calls for an improvement in the taste. It is conceivable to mask the bitterness of the active ingredient to reduce the discomfort, but masking is extremely difficult with a micronized active ingredient.
Powder inhaler medication, in which the active ingredients and carrier particles are fine powders, must in general contain an antistatic agent to prevent the each particles from adhesion and agglomeration. Japanese Patent Kohyo Publication No. H8-500109 (a Japanese translation of a PCT international application) describes that fatty acid esters are effective antistatic agents, but their being liquid requires a step for drying the carrier particles first before being mixed with the active ingredient, which makes it difficult to apply to a dry type preparation method. On the other hand, Japanese Patent Kohyo Publication No. H10-502647 (a Japanese translation of a PCT application) teaches a preparation method of a dry powder inhalation without using an antistatic agent by adjusting the particle size of the carrier particles to render them unadherable, but the particle size required is as large as 200 μm or larger. Japanese Patent Kohyo Publication No. H9-507049 teaches a dry type preparation method for a dry powder inhalation, but the method requires sieving once to remove fine powders from the carrier particle surface and it also calls for pulverizing the carrier particles by a ball mill.
Accordingly, it is an object of this invention to provide a dry powder inhalation of the type in which a pharmaceutically active ingredient is adhered to the surface of the carrier, that provides reduced adhesion-agglomeration tendencies during storage, that exhibits a high delivery fraction of the active ingredient to the lower respiratory tract, such as bronchiole and the like, that adheres less during inhalation to the powder dispersion device, that disperses well in the gas phase, and that has good inhalation capability.
It is another object of this invention to provide said dry powder inhalation with improvements during inhalation as to the taste and sense of discomfort in the oral cavity or the throat.
It is a further object of this invention to provide a preparation method which requires no complicated processes for readily preparing said dry powder inhalation in a simple manner.